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WO2008098976A2 - Procédé de fabrication d'implants pouvant être stockés et pourvus d'une surface ultrahydrophile - Google Patents

Procédé de fabrication d'implants pouvant être stockés et pourvus d'une surface ultrahydrophile Download PDF

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Publication number
WO2008098976A2
WO2008098976A2 PCT/EP2008/051764 EP2008051764W WO2008098976A2 WO 2008098976 A2 WO2008098976 A2 WO 2008098976A2 EP 2008051764 W EP2008051764 W EP 2008051764W WO 2008098976 A2 WO2008098976 A2 WO 2008098976A2
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WO
WIPO (PCT)
Prior art keywords
implant
ultrahydrophilic
bmp
peptides
metal
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/EP2008/051764
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German (de)
English (en)
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WO2008098976A3 (fr
Inventor
Herbert Jennissen
Steffen LÜERS
Markus Laub
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Individual
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Individual
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First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=39304780&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2008098976(A2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to US12/527,175 priority Critical patent/US9242029B2/en
Priority to AT08708969T priority patent/ATE503506T1/de
Priority to EP22193957.2A priority patent/EP4151245A1/fr
Priority to JP2009549828A priority patent/JP5390403B2/ja
Priority to HK10100586.8A priority patent/HK1136788B/xx
Priority to CA2678378A priority patent/CA2678378C/fr
Priority to EP19191782.2A priority patent/EP3590549B1/fr
Application filed by Individual filed Critical Individual
Priority to EP08708969A priority patent/EP2121058B1/fr
Priority to DE502008003007T priority patent/DE502008003007D1/de
Priority to AU2008214613A priority patent/AU2008214613B2/en
Publication of WO2008098976A2 publication Critical patent/WO2008098976A2/fr
Publication of WO2008098976A3 publication Critical patent/WO2008098976A3/fr
Anticipated expiration legal-status Critical
Priority to US14/949,994 priority patent/US10376613B2/en
Priority to US15/606,004 priority patent/US10369257B2/en
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/082—Inorganic materials
    • A61L31/088—Other specific inorganic materials not covered by A61L31/084 or A61L31/086
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/0095—Packages or dispensers for prostheses or other implants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/30—Inorganic materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/02—Inorganic materials
    • A61L31/022—Metals or alloys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/043—Proteins; Polypeptides; Degradation products thereof
    • A61L31/047—Other specific proteins or polypeptides not covered by A61L31/044 - A61L31/046
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05D—PROCESSES FOR APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05D1/00—Processes for applying liquids or other fluent materials
    • B05D1/18—Processes for applying liquids or other fluent materials performed by dipping
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
    • B65D81/00—Containers, packaging elements, or packages, for contents presenting particular transport or storage problems, or adapted to be used for non-packaging purposes after removal of contents
    • B65D81/18—Containers, packaging elements, or packages, for contents presenting particular transport or storage problems, or adapted to be used for non-packaging purposes after removal of contents providing specific environment for contents, e.g. temperature above or below ambient
    • B65D81/22—Containers, packaging elements, or packages, for contents presenting particular transport or storage problems, or adapted to be used for non-packaging purposes after removal of contents providing specific environment for contents, e.g. temperature above or below ambient in moist conditions or immersed in liquids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/102—Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • A61L2300/414—Growth factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings
    • A61L2300/608—Coatings having two or more layers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/18—Modification of implant surfaces in order to improve biocompatibility, cell growth, fixation of biomolecules, e.g. plasma treatment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/08—Coatings comprising two or more layers

Definitions

  • the present invention relates to a method for producing implants with an ultrahydrophilic
  • bioactive implant surfaces of metallic or ceramic materials which are used for implants such as artificial bones, joints, dental implants or even small implants, e.g. so-called stents, as well as implants further prepared by the methods, which allow, as so-called “delivery devices", a controlled release, for example via dissociation, of the bioactive molecules from the implant materials.
  • Procedures remain an implantation still a difficult and stressful operation, especially as it is associated with a lengthy healing process of the implant, which often includes months of hospital and spa stays including rehabilitation measures.
  • a lengthy healing process of the implant which often includes months of hospital and spa stays including rehabilitation measures.
  • the pain for the affected patients Length of treatment time and the separation of the familiar environment large loads.
  • the lengthy healing process caused by the required intensive care high personnel and care costs.
  • the first biological reaction is the adsorption of proteins on the surface of the biomaterial. In the resulting
  • Protein layer are then individual protein molecules, for example, by conformational changes to signal substances that are presented on the surface, converted or by catalytic (proteolytic) reactions are released as signaling substances acting protein fragments.
  • the cellular colonization takes place, a variety of cells such as leukocytes, macrophages, immunocytes, and finally tissue cells (fibroblasts, fibro-cysts, osteoblasts, Osteocytes).
  • tissue cells fibroblasts, fibro-cysts, osteoblasts, Osteocytes.
  • mediators such as cytokines, chemokines, morphogens, tissue hormones and real hormones play a crucial role.
  • integration of the implant into the whole organism occurs, and ideally a permanent implant is obtained.
  • BMP-I-BMP-15 bone morphogenic proteins
  • BMPs regulate the three key reactions of chemotaxis, mitosis and differentiation of the respective progenitor cell.
  • BMPs play an important role in embryogenesis, bone organogenesis and other tissues, targeting osteoblast cells, chondroblasts, myoblasts and vascular smooth muscle cells (proliferation inhibition by BMP-2).
  • BMPs including multiple isoforms. Except for the BMP-I, the BMPs belong to the "transforming growth factor beta” (TGF- ⁇ ) superfamily, for which specific receptors have been detected on the surfaces of the corresponding cells.
  • TGF- ⁇ transforming growth factor beta
  • BMP-7 Like the successful use of Recombinant human BMP-2 and / or BMP-7 has been shown to exhibit species specificity in experiments on disease repair processes in rats, dogs, rabbits and monkeys.
  • WO9926674 describes a method for producing bioactive implant surfaces of metallic or ceramic materials, in which anchor molecules are covalently bound to the surface of the implant material in a first step and in a second step peptides are covalently bound to the anchor molecules.
  • WO0209788 provides a method for producing bioactive implant surfaces of metallic or ceramic materials in which, in a first step, anchor molecules having hydrophobic residues are covalently bound to the surface of the implant material and in a second step peptides are applied to the implant material treated in this way due to non-covalent interactions between the peptides and the hydrophobic residues of the anchor molecules.
  • immobilization of peptides on metal surfaces in particular growth factors of the TGF class, e.g. BMP proteins, can be achieved if a sufficiently hydrophilic surface can be provided on the implant material.
  • the inventors have found that this can be achieved by producing an ultrahydrophilic oxide layer on the metal surface by treatment with an oxidizing agent.
  • the invention makes use of the fact that surfaces with a high surface energy can have a strong tissue bioadhesion. Since surfaces with a high surface energy usually have low contact angles with water, such a surface can be easily identified by measuring dynamic contact angles. Small contact angles characterize a high wettability of a surface.
  • a forward angle ( ⁇ ⁇ ⁇ r ) is distinguished from a retreat angle ( ⁇ jerk ), and the difference of these angles is referred to as the contact angle hysteresis.
  • the advancing angle is characteristic of the hydrophilicity-hydrophobicity properties of a surface and largely corresponds to the so-called static contact angle.
  • the greater the hysteresis the greater the heterogeneity of the surface.
  • Mechanically polished or electro-polished titanium surfaces normally have dynamic contact angles (advancing angles) of 70-80 ° and have, according to relevant literature less tissue bioadhesion. Therefore, according to the inventors' development, it is desirable to provide surfaces with low contact angles even on metals.
  • Titanium-based alloys are complex. It is believed that the surface of titanium metal spontaneously oxidizes in air and water, and then on the surface, that is, in the outermost atomic layer of the oxide, a reaction with water takes place to form hydroxyl groups.
  • the invention is therefore directed to a method of making an implant having an ultrahydrophilic surface, wherein the surface of the implant is treated with an oxidizing agent for an oxide layer on the surface of the metal until a contact angle hysteresis of less than 10 °, preferably less than 5 ° upon wetting of the surface of the implant with water, wherein the implant is selected from a material selected from the group of metals, the metallic alloys and combinations thereof with ceramic materials.
  • the metal implant preferably consists of a material which is selected from the group of metals, the metallic alloys and combinations thereof with ceramic materials.
  • the implant material used consists of metallic materials such as pure titanium or metallic titanium alloys, chromium / nickel / aluminum / vanadium / cobalt alloys (eg T1A1V4, TiAlFe2.5), stainless steels (eg V2A, V4A, chrome-nickel 316L) or a combination of which with ceramic materials such as hydroxyapatite, alumina, in which the metallic material is present as a composite material with ceramic material.
  • the surface of the metal implant is treated with an oxidizing agent to obtain an oxide layer on the surface of the metal until a contact angle hysteresis of less than 10 °, preferably less than 5 °, more preferably less than 1 °, more preferably from less than 0.5 ° on wetting with pure (distilled) water.
  • this treatment lasts until the contact angle hysteresis is in the range of the minimum in the diagram when plotting the contact angle hysteresis against the duration of the oxidation treatment.
  • concentrated sulfuric acid at a temperature of 15 ° C to 25 ° C by immersion.
  • implant-foreign metal ions eg chromium ions
  • the surface of the metal implant is washed in several washing steps (up to 15) with distilled water. If chromium ions can still be detected on the surface of the metal implant, then this can be done
  • Metal implant with a solution of a complexing agent be treated until no more metal ions are detectable.
  • the inventors have surprisingly found that, when using EDTA as the complexing agent, the solution turns violet to violet purple when chromium is dissolved out of the samples. Accordingly, the inventors propose that the samples be washed in 10% EDTA (1-3x) at pH 7, if necessary also in boiling EDTA solution, until chromium ion discoloration no longer occurs.
  • an implant having an ultrahydrophilic surface is thus obtainable, which can be made storable according to a further embodiment of a method according to the invention.
  • neutral salt solutions according to the invention can be used in solution of a single salt or else of various salts in a concentration and quantity which is inert to the ultrahydrohilic surface and sufficient, after evaporation, to cover the surface of the implant with the desiccation layer. Evaporation may be carried out when the implant is in the solution of neutral salt, or when the implant has been removed from the solution and thus covered only with a thin layer of this solution.
  • the "ultrahydrophilic" surface differs from the “hydrophilic” in that the former can be stabilized by methanol, ethanol and acetone. On the other hand, it can not be permanently stabilized by a 0.15 M NaCl solution, but only by a much higher concentration of 0.5 M or higher. In addition, the "hydrophilic" character of the surfaces becomes apparent
  • ultrahydrophilic surfaces can be stabilized by a desiccation layer, wherein it is quite conceivable that the hydrophilic surfaces can also lead to the stabilization of such a hydrophilic surface by the method of desiccation of solutions with non-volatile constituents described here.
  • the implant is placed in a saline solution which is inert to the ultrahydrophilic surface and which surrounds the implant on all sides.
  • a saline solution which is inert to the ultrahydrophilic surface and which surrounds the implant on all sides.
  • an implant produced in a different manner which has similar hydrophilicity properties with the above-mentioned contact angle hysteresis of less than 10 °, preferably less than 5 °, when wetted with water.
  • the salt solution may be a solution of a single salt or a combination of different salts in water, the salt being selected from the group consisting of the group of salts with an anion of SO 4 " , HPO 4 " , CH 3 COO “ , Cl, Br ⁇ , NO 4 ", ClO 4," I “, CNS”, ClCH 2 COO “, F 3 CCOO,” Cl 2 CHCOO “, Cl 3 CCOO,” Br 3 CCOO "or a cation selected from NH 4 + 'Rb +, K +, Na +, Cs +, Li +, Mg ++, Ca + +, Ba + +, and (CH 3) 4 N + / (C 2 H5) 4 N +, (C3 H7) 4 N + , (C 4 Hg) 4 N + .
  • a further development of the method according to the invention then comprises the additional step of placing the implant in a transportable package in the salt-containing solution having a total ion concentration of more than 0.5 mol / l, preferably more than 1 mol / l, and the transport packaging gas and liquid tight closes.
  • a moist packaging is also provided, which reliably protects the implant with an ultrahydrophilic surface from degradation of the ultrahydrophilia.
  • the implant in a saline solution without directly introducing it into a package, so temperature-friendly, without adversely affecting the implant properties, a process, in which the salty solution is evaporated to dryness.
  • the salt solution has a lower concentration than for the wet packaging, since the concentration in the course of the "evaporation" increases and exceeds the solubility of the salt when forming the Exsikkations für.
  • the saline solution is preferably used in in an amount and with a salt concentration which, after evaporation, yields a salt layer covering at least the ultrahydrophilic surface of the implant and having a layer thickness of preferably 1 to 500 ⁇ m.
  • the salt-containing solution gives, after evaporation, a salt layer surrounding the implant on all sides.
  • the resulting implant thus has the so-called desiccation layer, which covers and protects the ultrahydrophilic surface of the implant.
  • the implant provided with this desiccation layer can be placed in a dry package and stored for a long time.
  • sterilization of the implant is carried out, wherein the sterilization of the implant preferably comprises sterilization with electromagnetic radiation.
  • the invention is also directed to such a storable implant, which is available according to the various embodiments of the method according to the invention.
  • FIG. 1 shows a diagram of the magnitude of the advance or retreat angle versus the treatment time of a metal surface
  • FIG. 2 shows electron micrographs of an ultrahydrophilic, nanostructured surface on cp-titanium by the chromosulfuric acid process in various.
  • Fig. 3 is a graph showing the rate of release of BMP from variously treated metal surfaces
  • FIG 5 shows the EDX analysis of an ultrahydrophilic platelet with a desiccation layer after gamma fixation (A) and after removal of the desiccation layer with water (B).
  • the high surface energy leads to the adsorption of suitable proteins.
  • the chromosulfuric acid functionally produces an ultrahydrophilic surface and, in addition to the SLA microstructure, a "globular" nanostructure has arisen structurally.
  • the diameter of the interconnected nano-spheres is about 50-100 nm, with nanopores formed in the same order of magnitude.
  • peptides such as bone growth factors can be immobilized on these nanostructures by means of physisorptive or chemisorptive binding, presumably due to hydrophilic interactions on the implant material.
  • This makes it possible to form a chemotactically acting and / or biologically active, a so-called juxtakrine, implant surface, which is used for settlement,
  • active implants can be provided which also show a chemotactic effect on cells in the case of molecules released from the surface at a distance of 500 to 1000 ⁇ m, in the case of BMPs on osteoblasts.
  • sufficient loading of the oxidized metal surface is achieved by subjecting the peptides in a physiological buffer solution in a concentration sufficient to a loading of greater than 200 ng / cm 2 , preferably greater than 500 ng / cm 2 , and more preferably from more than 1000 ng / cm 2 of the peptide to achieve on the oxide surface of the metal implant applied.
  • this loading is associated with a physiological
  • the peptides are biomolecules which are advantageous for the biocompatibility of the implant, by counteracting possible rejection of the implant and / or promoting the ingrowth of the implant.
  • preferred peptides may be proteins from the class of TGF proteins, in particular bone growth promoting proteins from the class of
  • TGF transforming growth factor
  • TGF-ß Transforming Growth Factors beta
  • BMP Bone Morphogenetic Proteins
  • a protein of this class alone, in combination with other members of this class or together with biomolecules such as proteins of other classes or low molecular weight hormones or antibiotics can be used to improve the immune system.
  • biomolecules such as proteins of other classes or low molecular weight hormones or antibiotics
  • these further molecules can also be immobilized on the surface via cleavable bonds in the physiological environment.
  • the inventors have already found earlier that the number of oxide groups can surprisingly be increased by treating the surface of the metal with hot chromic sulfuric acid, preferably free from dregs. In contrast to the expectation that the metal dissolves under these conditions, it becomes
  • Transition metal surfaces such as titanium, steel, steel alloys such as Cr-Mo steel, or stainless steel or titanium surfaces refined with chromosulfuric acid are suitable materials for oxide treatment with dilute acid.
  • Both in polished and sandblasted (SLA surfaces) or with metal plasmas (eg titanium plasma spray, TPS) coated implants can ultrahydrophilic oxide layer after the treatment of the metal surface under defined conditions have a thickness of 10 nm to 300 nm and constructed in the form of nanostructures, as shown in Fig. 2, different geometries (for example, round or polygonal).
  • Pure titanium or titanium alloys eg TiAlV4, TiAlFe2.5
  • aluminum or stainless steel eg V2A, V4A, chrome-nickel 316L, Cr-Mo steel
  • the novel process according to the invention allows ultrahydrophilic surfaces to be prepared in all cases in contrast to previous processes.
  • the EDX detection limit is 0.2-0.5 at%.
  • the new chromium-free ultrahydrophilic surfaces show the particular new BMP-2 binding properties and stabilization of the salt layer shown below.
  • a thicker metal oxide layer (> 1000 nm) is to be provided on the metal surface and / or preferably an oxide layer with small micro- and nano-pores, the chromosulfuric acid described above with water to a density of 1.5 to 1.6 g / cm 3 diluted.
  • a "rough" surface layer with pits and pores is formed, such that the peptide loading available surface is increased.
  • the ultrahydrophilic surface produced by the chromosulfuric acid can lose its hydrophilic properties upon prolonged storage in air and in pure water.
  • the contact angle can rise to values of 20-40 ° after 1-2 hours under these conditions.
  • the ultrahydrophilic surface can according to the invention by means of a salt solution as
  • Stabilizing agents are stabilized.
  • Alcohols of the homologous alkane, alkene and alkyne series which may be straight-chain or branched and up to 20 carbon atoms, especially up to 6, can also be used as such stabilizing agents according to the invention
  • Carbon atoms in particular anhydrous methanol and ethanol, as well as phenolic compounds, the latter also in aqueous solution, can be used.
  • aqueous salt solutions which can be ranked according to their salting-out effect on proteins (Table 2). These are, for example, the anions SO 4 "” , HPO 4 " , CH 3 COO “ , Cl " ,
  • Tetraalkylammonium cations such as (CH 3 ) 4 N + > (C 2 Hs) 4 N + , (C 3 H 7) 4 N + , (C 4 H 9) 4 N +.
  • Such high salt concentrations are also formed from dilute buffer mixtures for short times during evaporation as indicated above.
  • the evaporation leads to dry to high local salt concentrations.
  • the HPO 4 - " which is much stronger aussalzende
  • the invention is therefore also directed to a method of rendering the implants with an oxide layer provided with nanostructures storage-stable with the aid of such "stabilizers".
  • the present invention also relates to a method of stabilizing the ultrahydrophilic surfaces by shielding the surfaces from influences that adversely affect ultrahydrophilicity.
  • an embodiment of the method according to the invention is also directed to the implant being given a solvent having a hydrophilic surface which contains dissolved therein a coating agent which adversely influences the ultrahydrophilic surface neither in the solution nor in the coating.
  • the solvent is evaporated and on the implant with the ultrahydrophilic surface, the coating remains behind and encloses the implant. In this way, the implant can be reliably preserved for long-term storage.
  • An embodiment of the solution with coating agent may be the above-described aqueous salt solution which is described in US Pat Evapormaschine easily ausaltsende properties.
  • Another embodiment may be a solution of a zwitterionic organic substance, for example an amino acid such as glycine be that similar salting-out, such as SO 4 ⁇ , HPO 4 can act ".
  • Other non-volatile organic substances can polyalcohols such as glycerol or monosaccharides such as glucose and disaccharides such as Sucrose as well as inositols which also have a strong influence on the water structure of a surface and give a coating after evaporation of the solvent.
  • the implants coated according to the invention have a long-term storage stability and, after washing the coating, can be made of salts or organic
  • Coating agent for loading with acting as mediators peptides are used.
  • the invention is also directed to a method for loading the surface of an implant with peptides, wherein the surface of the implant is given to peptides immobilized thereon due to physisorptive or chemisorptive interactions between the peptides and the ultrahydrophilic surface of the implant.
  • the peptides are used in a physiological buffer solution at a concentration which is sufficient, a loading of more than 200 ng / cm 2 , preferably more than 500 ng / cm 2 , and more preferably more than 1000 ng / cm 2 of the peptide to achieve the oxide surface of the metal implant.
  • the peptides are in a physiological buffer solution so in a concentration of more than 1 ug / ml, preferably more than 200 ⁇ g / ml buffer solution used.
  • growth factors from the class of TGF proteins in particular BMP proteins, preferably BMP-2 or BMP-7, which are vascular growth factors such as
  • VEGF vascular endothelial growth factor
  • angiotropin a substance that influences the rate of hemangiogenesis
  • ubiquitin a substance that influences the rate of hemangiogenesis
  • antibiotics a substance that causes hemangiogenesis
  • the invention is also directed to a method of making peptide coated implants wherein the implant having an ultrahydrophilic surface is treated with a preferably alkaline buffer solution containing one or more detergents.
  • a method may particularly include treatment with an NBS buffer of 125 mM NaBorate buffer, 0.066% sodium dodecyl sulfate (pH 10.0).
  • the invention is also directed to a method for loading implants with bone growth factors, in particular BMP-2, in which the ultrahydrohile surface of the implant is treated with a solution of the bone growth factor at a pH of 9 to 11, preferably 10.
  • a method for loading implants with bone growth factors in particular BMP-2, in which the ultrahydrohile surface of the implant is treated with a solution of the bone growth factor at a pH of 9 to 11, preferably 10.
  • an implant for example, from the Dry packaging taken implant, which is still covered with the desiccation layer, preferably directly with a buffered solution of bone growth factor at a pH of 9 to 11, preferably 10, treated without the Exsikkations Mrs must be previously washed off.
  • the inventors have thus succeeded in coating the ultrahydrohilen surface of an implant consisting of metallic materials such as pure titanium, metallic titanium alloys, chromium / nickel / aluminum / vanadium / cobalt alloys (eg TiAlV4, TiAlFe2.5), stainless steels (eg V2A , V4A, chromium-nickel 316L), ceramic materials, in particular hydroxyapatite, alumina, or combinations of the metallic materials with ceramic materials thereof, in which the metallic material is present as composite material with ceramic material, with bone growth factors, in particular BMP-2 in which the coating of the ultrahydrophilic surface of aqueous buffered solution is carried out either in the acid range in the range between pH 4 and 5, in particular at pH 4.5, or in the weakly alkaline range between pH 9 and 11, preferably pH 10.
  • Range can be advantageously carried out in the presence of detergents such as SDS.
  • a particularly preferred embodiment of the method according to the invention is designed in such a way that preference is given to the ultrahydrophilic surface of the implant BMP-2 or BMP-7m of a physiological buffer solution with a concentration of more than 1 ⁇ g BMP-2 or BMP-7 / ml buffer solution more than 200 ⁇ g BMP-2 or BMP-7 / ml buffer solution.
  • concentrations are usually sufficient, a loading of more than 200 ng BMP-2 or BMP-7 / cm 2 , preferably more than 500 ng BMP-2 or BMP-7 / cm 2 , and more preferably more than 1000 ng BMP-2 or BMP-7 / cm 2 of the peptide on the oxidized Surface of the metal implant to achieve.
  • the invention also relates to implants in which the implant material of titanium, titanium alloys, aluminum, stainless steel,
  • the implant may in this case be a joint or bone prosthesis, a dental implant or in particular one with a peptide, e.g. BMP-2, coated coronary stent (a so-called coronary stent, about 10 mm in length) to therapeutically prevent or ameliorate the late complication of restenosis caused by proliferation of vascular smooth muscle cells, thereby promoting healing and tolerability promote.
  • a peptide e.g. BMP-2
  • coated coronary stent a so-called coronary stent, about 10 mm in length
  • the influence of the materials modified by the method according to the invention on bone cells was investigated in animal experiments, the modified materials for this purpose were prepared in platelet or dumbbell shape. It was observed that 4 weeks after introduction into the animals, accelerated bone formation with contact to the implant surface by BMP-2 on the materials occurred.
  • the metals were purified by heating to 80 ° C. in 5% HNO 3 for 2 hours. After washing again in water, the platelets were dried by washing in 30 ml of dry methanol. Thereafter, they were either used directly or refined with chromosulfuric acid.
  • Example 1 Immobilization of rhBMP-2 on Ultrahydrophilic Titanium Platelets
  • the pretreated titanium platelets were incubated at 125 mM NaBorat buffer, 0.066% sodium dodecyl sulfate, pH 10.0, washed and equilibrated.
  • the effect of the salts takes place i.a. over the water structure.
  • the salts stabilize or destabilize the ultrahydrophilic surface via the water molecules and ionic groups bound to the titanium surface. Preference is given to NaCl salt solutions above 0.15 mol / l, more preferably above 0.5 M / l, most preferably in the range of 1 mol / l.
  • the scanning electron micrographs of chromosulfuric acid-treated SLA titanium flakes (14 ⁇ 14 ⁇ 1.5 mm) after gamma sterilization in desiccation buffer show a Mikrokavernen provided sterilized ultraphile titanium oxide surface with a protective layer of dried desiccation buffer, which gives a pure ultraphile titanium oxide surface after washing the "desiccation protective layer", as shown in Fig. 5, the EDX analysis of an ultrahydrophilic platelet with
  • the storage stability of the ultrahydrophilic surfaces is determined by the dependence of the dynamic contact angles of gamma-sterilized, ultrahydrophilic SLA titanium flakes provided with an inventive desiccation layer (14 x 14 x 1.5 mm) from the storage time shown in Table 4, SLA titanium flakes being understood to mean titanium flakes having sandblasted and acid etched surfaces. As shown, an "unprotected" hydrophilic surface is less hydrophilic after only a few hours in air, while the contact angles of gamma-sterilized, ultrahydrophilic SLA titanium flakes provided with the desiccation layer of the present invention are nearly unchanged at 0 ° after storage for up to 24 weeks.

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Abstract

La présente invention concerne un procédé de fabrication d'implants pourvus d'une surface ultrahydrophile, les implants ainsi fabriqués, et des procédés de fabrication de surfaces d'implants chargées bioactives en matériau métallique ou céramique qui sont utilisées pour des implants tels que des os et des articulations articifiels, des prothèses dentaires ou également de très petits implants tels que des stents. Elle concerne en outre des implants fabriqués selon ledit procédé qui permettent, en tant que dispositifs dits d'administration, une libération prolongée, par ex. par dissociation, des molécules bioactives des matériaux de l'implant.
PCT/EP2008/051764 2007-02-14 2008-02-13 Procédé de fabrication d'implants pouvant être stockés et pourvus d'une surface ultrahydrophile Ceased WO2008098976A2 (fr)

Priority Applications (12)

Application Number Priority Date Filing Date Title
DE502008003007T DE502008003007D1 (de) 2007-02-14 2008-02-13 Verfahren zur herstellung von lagerfähigen implantaten mit einer ultrahydrophilen oberfläche
EP08708969A EP2121058B1 (fr) 2007-02-14 2008-02-13 Procédé de fabrication d'implants pouvant être stockés et pourvus d'une surface ultrahydrophile
EP22193957.2A EP4151245A1 (fr) 2007-02-14 2008-02-13 Procédé de fabrication d'implants dotés d'une surface ultrahydrophile
JP2009549828A JP5390403B2 (ja) 2007-02-14 2008-02-13 超親水性表面を有する貯蔵可能なインプラントの製造方法
HK10100586.8A HK1136788B (en) 2007-02-14 2008-02-13 Method for producing implants with an ultrahydrophilic surface
CA2678378A CA2678378C (fr) 2007-02-14 2008-02-13 Procede de fabrication d'implants pouvant etre stockes et pourvus d'une surface ultrahydrophile
EP19191782.2A EP3590549B1 (fr) 2007-02-14 2008-02-13 Procédé de fabrication d'implants dotés d'une surface ultrahydrophile
US12/527,175 US9242029B2 (en) 2007-02-14 2008-02-13 Method for producing implants with an ultrahydrophilic surface
AU2008214613A AU2008214613B2 (en) 2007-02-14 2008-02-13 Method for producing implants with an ultrahydrophilic surface
AT08708969T ATE503506T1 (de) 2007-02-14 2008-02-13 Verfahren zur herstellung von lagerfähigen implantaten mit einer ultrahydrophilen oberfläche
US14/949,994 US10376613B2 (en) 2007-02-14 2015-11-24 Process for the production of storable implants with an ultrahydrophilic surface
US15/606,004 US10369257B2 (en) 2007-02-14 2017-05-26 Process for the production of storable implants with an ultrahydrophilic surface

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DE102007007865A DE102007007865A1 (de) 2007-02-14 2007-02-14 Verfahren zur Herstellung von lagerfähigen Implantaten mit einer ultrahydrophilen Oberfläche
DE102007007865.1 2007-02-14

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US14/949,994 Continuation US10376613B2 (en) 2007-02-14 2015-11-24 Process for the production of storable implants with an ultrahydrophilic surface

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AT (1) ATE503506T1 (fr)
AU (1) AU2008214613B2 (fr)
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US10251975B2 (en) 2009-02-19 2019-04-09 Neoss Limited Surface treatment process for implantable medical device
WO2012175218A1 (fr) * 2011-06-24 2012-12-27 Straumann Holding Ag Corps constitué d'un matériau de céramique
US9649407B2 (en) 2011-06-24 2017-05-16 Straumann Holding Ag Body made of a ceramic material
US9724274B2 (en) 2011-06-24 2017-08-08 Straumann Holding Ag Body made of ceramic material
EP2744529B1 (fr) 2011-10-21 2020-07-15 Straumann Holding AG Procédé de fourniture de structures pour adhérence améliorée de protéine à la surface d'un corps
EP2790743B1 (fr) 2011-12-16 2018-06-06 Herbert P. Prof. Dr. Jennissen Implant à surface microstructurée et ses procédés de fabrication
WO2018189185A1 (fr) 2017-04-11 2018-10-18 Straumann Holding Ag Implant dentaire
US12521211B2 (en) 2017-04-11 2026-01-13 Straumann Holding Ag Dental implant
WO2022090530A1 (fr) 2020-11-02 2022-05-05 Institut Straumann Ag Implant dentaire

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ES2361895T3 (es) 2011-06-24
DE102007007865A1 (de) 2008-08-21
ES2929432T3 (es) 2022-11-29
KR20090117807A (ko) 2009-11-12
US20160136336A1 (en) 2016-05-19
EP3590549A1 (fr) 2020-01-08
US20100168854A1 (en) 2010-07-01
EP4151245A1 (fr) 2023-03-22
JP5390403B2 (ja) 2014-01-15
US10369257B2 (en) 2019-08-06
US20170258969A1 (en) 2017-09-14
EP2121058B1 (fr) 2011-03-30
CA2678378A1 (fr) 2008-08-21
EP2428232A3 (fr) 2014-06-25
AU2008214613A1 (en) 2008-08-21
US9242029B2 (en) 2016-01-26
EP2121058A2 (fr) 2009-11-25
JP2010517729A (ja) 2010-05-27
EP2428232A2 (fr) 2012-03-14
US10376613B2 (en) 2019-08-13
DE502008003007D1 (de) 2011-05-12
CA2678378C (fr) 2015-11-24
WO2008098976A3 (fr) 2009-07-23
ATE503506T1 (de) 2011-04-15
AU2008214613B2 (en) 2011-09-01
EP3590549B1 (fr) 2022-09-07
HK1136788A1 (en) 2010-07-09

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